PROJECT SUMMARY The Candidate, Michael E. Watson, M.D., Ph.D., is a faculty member (Assistant Professor) of the Division of Pediatric Infectious Diseases at the University of Michigan. He completed a residency in Pediatrics and fellowship in Pediatric Infectious Diseases at Washington University where he began his research on the bacterial pathogen Streptococcus pyogenes under the guidance of Michael Caparon, Ph.D., Professor of Microbiology. In July 2013 he was recruited to the University of Michigan and immediately appointed as a faculty scholar to the Child Health Research Center (CHRC) K12 Career Development Award which funded Dr. Watson for 3 years. The Immediate Goal of this K08 Award is to provide an additional 3 years of research experience protected from clinical and administrative duties (?75% research effort) in order to acquire further training in the investigation of bacterial pathogenesis related to colonization and infection at mucosal sites and the use of advanced genomic analysis methodology. The Long-Term Goal is to become an independent, extramurally-funded, pediatric physician-scientist. The Research Environment at the University of Michigan is exceptional and currently ranks 9th among all research-oriented medical schools according to the 2017 US News and World Report. The Candidate has developed a comprehensive Career Development Plan. Dr. Watson has recruited co-mentors including Harry L.T. Mobley, Ph.D., Professor of Microbiology, and Suzanne R. Dawid, M.D., Ph.D., Associate Professor of Pediatric Infectious Diseases and Microbiology. Dr. Mobley has a distinguished career of >30 years in microbial pathogenesis research and has previously mentored >33 fellows and junior faculty members. Dr. Dawid provides expertise in streptococcal bacterial pathogenesis and mucosal colonization. Dr. Watson has established a Scientific Advisory Subcommittee for technical expertise and a Career Advisory Subcommittee composed of senior clinician-scientists from Pediatrics who will help him navigate an academic medicine career. In addition, Dr. Caparon at Washington University will continue serving as an external advisor. Research Strategy: The Central Hypothesis is that S. pyogenes persister strains successfully evade host mucosal immunity by negatively regulating the expression of virulence factors or antigens necessary for the activation of cytokine IL-17A-mediated leukocyte recruitment. The Specific Aims are: 1) Identify and characterize host leukocyte populations necessary to promote streptococcal mucosal clearance; and 2) Characterize streptococcal persister strains in mucosal epithelial tissues. The proposed work is innovative, capitalizing on the use of a long-term, mucosal carriage murine model for S. pyogenes developed by the Candidate, combined with transcriptomic and metabolomic profiling to characterize streptococcal persister strains in vivo. The Rationale is that through this proposed work it may be possible to develop novel strategies to stimulate mucosal immunity, or specifically target the metabolic activities of long- term persister strains, to promote streptococcal eradication from the mucosal epithelial environment.